Sex-biased neurodevelopmental disorders, including schizophrenia, have been associated with maternal stress experienced during pregnancy. We have recently identified a specific period of early pregnancy where male offspring were sensitive to the effects of maternal stress, displaying as adults behaviors and stress physiology suggestive of brain feminization. Our hypothesis to be examined in these proposed studies is that prenatal stress exerts programming effects on the developing male brain via changes in methylation patterns affecting testis development and testosterone production during the organizational period of sexually dimorphic brain development. Organizational and activational testosterone has been shown to be important in programming of male stress neurocircuitry. Stress pathway dysregulation and sensitivity is a hallmark of most neuropsychiatric disorders. Therefore, these studies are designed: 1) To determine the contribution of SRY gene methylation and expression in the programming of a feminized stress-sensitive phenotype of early prenatal stress male mice, 2) To examine the heritability of early prenatal stress effects in second generation offspring to identify possible gene targets of PNS that may be epigenetically modified in the germline, and 3) To utilize prenatal testosterone treatment or DNMT1 inhibition to ameliorate the effects of early prenatal stress on male offspring stress sensitivity. Determination of the fetal antecedents and mechanisms by which alterations in brain development of these circuits occur, and identification of potential heritable aspects of this phenotype may provide insight into novel therapeutic targets and disease prevention. PUBLIC HEALTH RELEVANCE: Sex-biased neurodevelopmental disorders, including schizophrenia, have been associated with maternal stress experienced during pregnancy. We have recently identified a specific period of early pregnancy where male offspring were sensitive to the effects of maternal stress, displaying as adults behaviors and stress physiology suggestive of brain feminization. Our hypothesis to be examined in these proposed studies is that prenatal stress exerts programming effects on the developing male brain via changes in methylation patterns affecting testis development and testosterone production during the organizational period of sexually dimorphic brain development.